Preparation of tocopherols



United States Patent (9 3,187,011 PREPARATIQN F TGCGPEEROLS Frank J. Sevigne, Tarrytown, N.Y., assignor, by mesne assignments, to General Mills, line, Minneapoiis, Minn, I a corporation of Delaware No Drawing. Filed Aug. 28, 1961, Ser. No. 134,142

The portion of the term of the patent subsequent to Aug. 29, 1978, has been disclaimed 7 Claims. (Cl; 260345.5)

This application is a continuation-in-part of Serial No. 763,450, filed September 26, 1958, now US. Patent No. 2,998,430, issued August 29, 1961.

This invention relates to a process for the conversion of tocopheryl compounds from non-useful mixture to a biologically useful condition and, in particular, is concerned with the conversion of tocopherol isomers to useful alpha form.

As is well known, alpha tocopherol has high vitamin E activity, while non-alpha tocopherols, such as beta, gamma and delta, have much lower activity. Since the non-alpha forms predominate in nature many attempts have been made to convert them to the more biologically active alpha form. The non-alpha tocopherols differ from the alpha only in that one or both methyl groups are missing from the 5-7 positions. Attempts at conversion in thepast have involved the direct methylation of the nonalpha tocopherols and have been reasonably successful.

This invention provides a method for the conversion of non-alpha tocopherol compounds to the alpha form, which is characterized by a sequence of steps comprising, first, oxidizing the compounds to quinone form and opening the chroman ring, reducing said quinone form to hydroquinone, thereupon haloalkylating the said compounds, then reclosing the ring to give the desired alpha tocopherol. The process is thus characterized by the sequence and combination of steps involved in the process, all of which are carried out under very mild conditions, which result in minimum formation of impurities and side reactions, the process being further characterized by the smoothness and ease with which it takes place in each step and the high yields obtained at each step in the operation.

The process of the present invention may be carried out with non-alpha tccopherols in various forms. It may be carried out with the various pure non-alpha tocopherols, i.e., B, 6, or it may be carried out with impure mixtures of inert materials containing varying, even small, amounts of the tocopherols or tocols. For instance, it may be carried out with by-products resulting from the refining of vegetable oils. Hot well sludge from the steam refining of vegetable oils, soybean oil, corn oil, wheat germ oil, peanut oil, cottonseed oil andthe like, are sources of the deodorizer sludge. Wheat carries variable but significant amounts of the tocopherol compounds.

A summary of the variants of tocopherol and the tocols to which the process is applicable is found in British Patents 809,895 and 827,391, which disclosures are fully incorporated herein. It will be understood that the several steps of the invention may be carried out in different ways with dillerent raw materials and under modified conditions to suit the particular raw material being processed.

In summary, therefore, the process may be illustrated by the following sequence of reactions.

EXAMPLE I C'hloromethylation of pure 'y-tocopheryi hydroquinone having a purity of 99.1% as determined by the Emmeric- Engel assay were dissolved in 210 ml. of ethyl alcohol.

hldlll To this solution was added 25 grams of FeCl .6I-I O dissolved in 180 ml. of ethyl alcohol. The mixture was stirred for 10 minutes at room temperature and then refluxed for an additional ten minutes. The mixture was cooled, 1000 ml. of water were added and the aqueous mixture extracted successively with 600 ml., 400 ml. and 400 mLportions of ethyl ether. The combined ethyl-ether solutions were washed five times with 400 ml. portions of distilled water, dried over anhydrous sodium sulfate, and the solvent removed under vacuum. A reddish-yellow oil was obtained as a residue (10.2 gms.) having E g 260 mn.=oll

The -tocopheryl quinone (10.0 gms.) was taken up in ml. of methanol and placed in a hydrogenation apparatus and hydrogen bubbled through in the presence of Raney nickel as a catalyst for 1 hour. The catalyst was filtered off; the methanol solution diluted with 200 ml. of water, and then extracted successively with three 200 ml. volumes of ethyl ether. The combined ether extracts were washed three times with 200 ml. portions of water, dried with sodium sulfate and the ethyl ether removed under vacuum. The resulting 'y-tocopherol hydroquinone (8.9 gms.) assayed 94% pure by the Emmerie-Engel assay.

The above described reaction, extraction and washing steps were done under subdued light to prevent distribu tion of the sensitive quinone and hydroquinone compounds. In the reduction of gamma tocopheryl quinone to gamma-tocopheryl hydroquinone, thefollowing reducing substances can be used: (1) alkali metal hydrosulphites such as potassium hydrosulphite and sodium hydrosulphite; (2) the alkali metal hydrides and borohydrides such as lithium aluminum hydride, sodium borohydride, and potassium borohydride; (3) hydrogen gas in the presence of a suitable hydrogenation catalyst, such as palladiurn on a carbon or calcium carbonate carrier, Raney nickel, etc.

For the oxidation of gamma tocopherol to gamma tocopheryl quinone, the following oxidizing agents are satisfactory: ferric chloride, gold chloride, silver nitrate and ceric sulphate. I i

(b) CHLOROMETHYLATION 0F IOCOPHERYL HYDROQUINONE Gamma-tocopheryl hydroquinone (8.34 gms.) was dissolved in ml. of anhydrous ethyl ether. Chloromethyl ether (2.25 ml.) was added and the ether solution refluxed for 1 /2 hours. The'chloromethyl ether and ethyl ether were removed under vacuum yielding a dark reddish oil- (8.59 grns.). When a sample of this oil was fused with sodium metal, a positive test for chloride ion was obtained with silver nitrate solution.

6.37 gms. of the gamma tocopheryl chloromethylated hydroquinone was dissolved in 50 ml. of ethyl ether. 10.5

ml. of 36% HCl was added and to the mixture, 3.6 gms. of zinc dust was slowly added and the reaction allowed to proceed for one hour. The ether layer was eparated, washed with Water until chloride free, dried with anl1y drous sodium sulfate, and the ether evaporated under vacuum to yield a light yellow oil (6.10 gins). Fusion of a sample of oil with sodium metal and treatment with AgNO solution gave a negative test for chloride ion.

(d) CYLCIZATION WITH STANNOUS CHLORIDE 6.0 grns. of the reduced hydroquinone was dissolved in 35 ml. of 1,4 dioxane; 3.55 gms. of SncL li-l O and 5 m1. of 36% HCl were added and the mixture refluxed for 7 /2 hours at 92 C. The mixture was cooled to room temperature, 100 ml. of water added and the aqueous mixture extracted with 20 ml, 30 ml. and 35 ml. portions of petroleum ether. The petroleum ether solution was V tered, and the solvent distilled off under vacuum.

washed five times with; 60 ml. portions. of distilled water,

' driedwith sodium sulfate, and the petroleum ether removed under vacuum. A light orange oil (5.7 gms.) was btained whichassayed 68% total tocopherols of which 91% was in the form of alpha-tocopherol. The chem ical structure was further proved by conversion to the acid succinate ester which gave a product melting at 765 (3.,

identical withthat of alpha tocopheryl acid succinate.

r 7 EXAMPLE 1r iC hloromethyla tiorr .of beta-rocophe'tyl hydroquinane 0.1 gm. of'pure beta-tocopherol was dissolved in 5 ml. of methyl alcohol. A solution containing 0.25 gmaof I The quinone (0.09 gm.) was suspended in 8 ml. of

'methyl alcohol and to the mixture was added 0.2 gm. of

sodium hydrosulfite in 1 m1. of water. The mixture was shaken .for 30 minutes, diluted with 20 ml. ofwater and 1 extracted three times with 100 ml. portions of ethyl ether.

The ether solution of the resulting delta-tocopheiyl hydroquinone'was ,dr'ed in the usual manner with sodium sulfate. a

Fe-CI .6H O in 5 ml. of methyl alcohol was added dropwise over a period of fifteen minutes and the mixture was The mixture then refluxed for an additional 5 minutes. i was diluted with 20 ml. of distilled Water, cooled to room temperature and extracted with ml., 10 ml. and 10 ml..

portions of ethylether. The combined ether solutions were washed five times with water, dried with anhydrous sodium sulfate, filtered and the solvent removed under I vacuum. The residue consisted of a reddish-yellow oil.

'The beta-tocopheryl quinone (0.08 gm.) wa's suspended in 5 ml. of methyl alcohol and to the mixture was added 0.2 'gm. of sodium hydros-ulfite in 1 ml. of Water. The

To the ethyleth'er solution was added 0.5 ml. concentratedhyd'rochloric acid and 0.2 ml. Formalin. The mixture was stirredv-igorously for two hours under nitrogen.

To the resulting ether solution of the chloromethylated hydroquinone'was added 0.4 ml. of concentrated hydr0- chloric acid' and'1.0 gm. of zinc dust was also added over a-ten minute period with stirring. The reaction was con-' The ether layer'was decanted from theacid solution and zinc residue, washed ten times with 10ml. portions of water, dried over sodium sulfate, and

tinned for two hours.

the solvent removed under vacuum. Theresidue consisted of a pale yellow oil (0,088 grin).

' The hydroquinone (0 .088, gm.) was dissolved in ml.

' of dioxane and reflux-ed for six hours unde rnitrogen with 0.2 gm. stannous chloride and 0.15 rnl'..concentrated hydrochlor-ic acid. The mixture was diluted with 10 ml.

mixture was shaken for 40 minutes, diluted with 20 ml.

of water and extracted twice with l0.ml. p'ortionsv of ethyl ether- The ether solution of the resulting beta-tocopheryl hydroquinone was dried in the usual manner with sodium sulfate; a

. To'the ethylether solution was added 0.2 ml; of concentrated hydrochloric acid and 0.1 gm. of p-araformaldehyde." The mixture was stirred under nitrogen for three hours. Two-tenths. (0.2) gm. of concentrated .hydro chloric acid waszadded and then 0.25 'gm. of zinc dust added'slowly over a 30 minuteperiod. The mixture was stirred foran additional 'pe-riod o--1 hour. The mixture was then extracted three times with 10 ml. portions of ethyl ether. The ether extracts were combined, washed four times with 5 mlJportions of'distilled water, dried over sodium'sulfate, filtered, and the solvent removed.

under vacuum. .The reduced chloromethylated product (0.55 gm.) was water and extracted three times with 10 ml. portions of ethylethern The combined extracts were washed with water, dried'over sodium sulfate, and the -ether;removed under vacuum. I I f The. resulting yellow'oil contained 78% total tocopherols according to chemical assay. 7 The alpha to'copherol resulting-yellow oil contained 46% total tocophero'ls'by chemical assay. 'I'healpha tocopherol content was 44% as indicated by chemical assay according to the method dissolved in 5 ml; of glacial acetic acid. Hyd-robromic 7 acid (0.5 ml.) andzincdust (0.2 gm.) were added and the mixture refluxed for 10 minutesunder nitrogen. After diluting with 40 ml. of water, the acid solution was ex:

tracted three times with 30 ml. portions of ethylether. The combined ether extracts were Washed twice with 10 ml. portions of 2 N Na CO solutionand then six times with 10 ml. portions. of distilled water. The ether solution was dried over sodium sulfate, filtered, and the solventremoved under vacuum. The residue consisted of a pale yellow oil containing 57 percent alpha-tocopherol according to chemical assay.

EXAMPLE III I p 'Chloromethylation of delta-tocopheryl hydroquinone One-tenth (0.1) gm. of pure delta-tocopherol wa dissolved in 5 ml. of absolute methyl alcohol. 7

of 0.25 gm. of FeCl .6H O in 5 ml. ofmethyl alcoholwas added drop-wise over a period of fifteen minutes. Twenty A solution (20) ml. of distilled water were added and the mixture Textracted three times with 20 ml. portions of ethyl ether.

The combined extracts were washed five. times with 10 m1. portions of distilled water, dried withsodium sulfate, fil- T-he reddish-yellow oil obtained was subjectedto a sec- 0nd oxidation under identical conditions. The oxidizing solution was diluted with water andextracted three times with 20 ml. portions, of ethyl ether. j'The. combined ex- Although the invention has been described with reference to a limited number of examples, it is to be undertracts were washed with distilled water, dried over sodium sulfate, filtered, and the solvent removed under vacuum. T he resulting delta-tocopheryl quinone appeared as a red 7 oil."

of uartermaster. Chem., 175, 605, 1943 In the extra-ctionof tocopherylquinone reaction prod i not in the first stage ethylether is used, because that has 7 the advantage offbeing a'good solvent immiscible with water and elfective for' the purpose. However, other ethers, suchas methylethyl ether may be used, because the basicrequirement' is high solvent capacity forthe tocopheroL' a In the chlorornethylation phase ofithe operations, the solvent used was ethyl ether in the several examples, but

it is to be understood; of course, that any solvent for the reactants would be'useful. Here methyl ether or methylethyl ether-will serve the purpose. In the actual chloromethylation which is conducted, the formaldehyde and hydrogen chloride may be used in the gaseous form, or the formaldehyde may be used in the solid pa'raldehyde form.

Similarly, the reducing agent is zinc dust and hydrochoric acid because it is a convenient one, but actually any pair of reactants, forjexample, a Zinc amalgam is suitable for forming the nascent hydrogen.

i In the cyclizationstep of reaction, glacial acid hydro.-

chloric acid and Zinc dust were used; The reactions were specific but it is to'be understood that :any reactants usable for the purpose of closingthe chroman ring might be used.

stood variations thereof may be practiced without departing from the spirit or scope of the invention.

What is claimed is: a 1

1. The process of convertinga tocopherol compound; in a.sourceimaterialv extracted from a natural source, to

alpha tocopherol form, comprising, oxidizing said material containing said tocopherol compound whereby the chroman ring opens forming a tocopheryl par-a quinone, reducing said product to hydroquinone form, ehlorornethylating said parahydroquinone, whereby any hydrogen atoms present on the phenyl ring are replaced with chloromethyl radicals, reducing said compound whereby the chloromethyl radicals are converted to methyl radicals, and closing the ring of said compound whereby alpha tocopherol is produced.

2. The process of claim 1 wherein the tocopherol compound is a compound selected from the group consisting of beta, gamma, delta tocopherols and mixtures thereof.

3. The process of claim 1 wherein the oxidation step is conducted by reacting the tocopherol with ferric chloride.

4. The process of claim 1 wherein the chloromethyl-ation step is conducted by reacting the hydroquinone with a formaldehyde yielding material and hydrochloric acid.

5. The process of claim 1 wherein the reduction step is conducted by reacting the chloromethylated product with zinc dust and hydrochloric acid.

6. The process of claim 1 wherein the cyclization step is conducted with stannous chloride.

7. The process of claim 1 wherein the cyclization step is conducted with zinc chloride.

References Cited by the Examiner UNITED STATES PATENTS 2,314,887 2/43 Tishler et -al Q 6034'S .15 2,592,628 4/52; Weisler 260345.5 2,998,430 8/61 Sev-igne 26035.5

WALTER A. MODANCE, Primary Examiner.

I. MARCUS, Examiner.

Dedication 3,187,011.F1'an7c J. Sevigne, Tarrytown, NY. PREPARATION OF TO- COPHEROLS. Patent dated June 1, 1965. Dedication filed May 20, 1976, by the assignee, Geneml Mills, Inc. Hereby dedicates to the, Public the remaining term of said patent.

[Oyfice'al Gazette July 2'7, 1.976.] 

1. THE PROCESS OF CONVERTING A TOCOPHEROL COMPOUND, IN A SOURCE MATERIAL EXTRACTED FROM A NATURAL SOURCE, TO ALPHA TOCOPHEROL FORM, COMPRISING OXIDIZING SAID MATERIAL CONTAINING SAID TOCOPHEROL COMPOUND WHEREBY THE CHROMAN RING OPENS FORMING A TOCOPHERYL PARA QUINONE, REDUCING SAID PRODUCT TO HYDROQUINONE FORM, CHLOROMETHYLATING SAID PARAHYDROQUINONE, WHEREBY ANY HYDROGEN ATOMS PERSENT ON THE PHENYL RING ARE REPLACED WITH CHLOROMETHYL RADICALS, REDUCING SAID COMPOUND WHEREBY THE CHLOROMETHYL RADICALS ARE CONVERTED TO METHYL RADICALS, AND CLOSING THE RING OF SAID COMPOUND WHERBY ALPHA TOCOPHEROL IS PRODUCED. 